1. Field of the Invention
The present invention relates to methods for treating solid tumors, in particular those pertaining to the extended release of an antineoplastic agent from biodegradable compositions.
2. Description of the Prior Art
Antineoplastic agents, such as paclitaxel, have been used to treat solid tumors of various types. For example, those in the art have attempted to administer a variety of antineoplastic agents into the tumor itself (xe2x80x9cintralesionallyxe2x80x9d, also called xe2x80x9cintratumorallyxe2x80x9d) in the form of an aqueous slurry. See Luck et al., U.S. Pat. No. 4,978,332. However, such water-based compositions also require the presence of a vasoconstrictive drug to localize the action of the agent.
An opposite approach has also been taken by formulating a water immiscible, fatty acid ester matrix for intratumoral injection, e.g., of paclitaxel. See WO 95/17901 published Jul. 6, 1995 and Brown et al., U.S. Pat. No. 5,573,781. However, the controlled intratumoral release of the antineoplastic agent in a lipid carrier over a prolonged period of time, for example, at least three or four weeks, has not been disclosed.
Thus, there exists a need for a method of effecting the in vivo, controlled release of a variety of different antineoplastic agents into a solid tumor, whether they are small hydrophobic drugs, such as paclitaxel, or large and bulky bio-macromolecules, such as therapeutically useful proteins. The effective release of the antineoplastic agent preferably occurs without requiring the presence of significant amounts of a physiologically acceptable fluid vehicle, such as normal saline or a water-immiscible organic solvent.
Biocompatible polymeric materials have been used in various therapeutic drug delivery and medical implant applications. If a medical implant is intended for use as a drug delivery or other controlled-release system, using a biodegradable polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al., xe2x80x9cChemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agentsxe2x80x9d, J. Macro. Science, Rev. Macro. Chem. Phys., C23(1), 61-126 (1983). In this way, less total drug is required, and toxic side effects can be minimized.
Polymers have been used for some time as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., xe2x80x9cPolymeric Controlled Drug Deliveryxe2x80x9d, Advanced Drug Delivery Rev., 1:199-233 (1987); Langer, xe2x80x9cNew Methods of Drug Deliveryxe2x80x9d, Science, 249:1527-33 (1990) and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity. Examples of classes of synthetic polymers that have been studied as possible solid biodegradable materials include polyesters (Pitt et al., xe2x80x9cBiodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applications to Contraceptives and Narcotic Antagonistsxe2x80x9d, Controlled Release of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al. xe2x80x9cTrends in the Development of Bioresorbable Polymers for Medical Applicationsxe2x80x9d, J. Biomaterials Appl., 6:1, 216-50 (1992); polyurethanes (Bruin et al., xe2x80x9cBiodegradable Lysine Diisocyanate-based Poly(Glycolide-co-xcex5 Caprolactone)-Urethane Network in Artificial Skinxe2x80x9d, Biomaterials, 11:4, 291-95 (1990); polyorthoesters (Heller et al., xe2x80x9cRelease of Norethindrone from Poly(Ortho Esters)xe2x80x9d, Polymer Engineering Sci., 21:11, 727-31 (1981); and polyanhydrides (Leong et al., xe2x80x9cPolyanhydrides for Controlled Release of Bioactive Agentsxe2x80x9d, Biomaterials 7:5, 364-71 (1986).
More specifically, Walter et al., Neurosurgery, 37:6, 1129-45 (1995) discloses the use of the polyanhydride PCPP-SA as a solid carrier for intratumoral administration. Others have used poly(lactic acid) as intratumoral solid carriers, for example, as needles for injection directly into the lesion. See Kaetsu et al., J. Controlled Release, 6:249-63 (1987); and Yamada et al., U.S. Pat. No. 5,304,377.
However, others have encountered problems with these materials. Paclitaxel has been encapsulated in poly(epsilon-caprolactone), but only about 25% of the drug was released over 6 weeks in in vitro assays. Dordunoo et al., xe2x80x9cTaxol Encapsulation in Poly(epsilon-caprolactone) Microspheresxe2x80x9d, Cancer Chemotherapy and Pharmacology, 36:279-82 (1995). Poly(lactic-co-glycolic acid) microspheres have been used for the encapsulation of paclitaxel and exhibited a relatively constant release rate over three weeks in vitro, but these formulations were not evaluated in vivo. Wang et al., xe2x80x9cPreparation and Characterization of Poly(lactic-co-glycolic acid) Microspheres for Targeted Delivery of a Novel Anticancer Agent, Taxolxe2x80x9d, Chemical and Pharmaceutical Bulletin, 44:1935-40 (1996). Paclitaxel has also been encapsulated in polyanhydride discs, but the resulting release rate has been described as too slow for clinical utility. Park et al., xe2x80x9cBiodegradable polyanhydride Devices of Cefaxolin Sodium, Bupivacaine, and Taxol for Local Drug Delivery: Preparation and Kinetics and Mechanism of in vitro Releasexe2x80x9d, J. of Controlled Release, 52:179-89 (1998).
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: xe2x80x9cPhosphorus-Containing Polymersxe2x80x9d, (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, are as follows: 
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or Rxe2x80x2 group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with xe2x80x94O-carboxy groups may be coupled to the phosphorus via a phosphoester bond, which is hydrolyzable. See, Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765. The P-O-C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
Copending U.S. patent application Ser. No. 09/053,648 filed Apr. 2, 1998, which corresponds to PCT/US98/0681 (published Oct. 8, 1998 as WO 98/44021), discloses biodegradable terephthalate polyester-poly(phosphate) compositions. Copending patent application Ser. No. 09/053,649 filed Apr. 2, 1998, which corresponds to PCT/US98/06380 (published Oct. 8, 1998 as WO 98/44020), discloses biodegradable compositions containing polymers chain-extended by phosphoesters. Further, copending application Ser. No. 09/070,204 filed Apr.30, 1998, which corresponds to PCT/US98/09185, discloses biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds. However, none of these disclosures suggests the specific use of biodegradable poly(phosphoester) compositions for the intratumoral treatment of solid tumors.
Thus, there remains a need for new methods and materials for the difficult problem of successfully treating tumors with a minimum of toxicity and avoiding prolonged courses of periodic re-dosing.
It has now been discovered that biodegradable polymer compositions comprising:
(a) a poly(phosphoester) biodegradable polymer and
(b) at least one antineoplastic agent in an amount effective to inhibit the growth of a solid tumor
are suitable for intratumoral administration to treat a mammal having a solid tumor. In a preferred embodiment, the composition comprises:
(a) a poly(phosphoester) biodegradable polymer made by the process of reacting a phosphorodihalidate and a diol; and
(b) at least one antineoplastic agent in an amount effective to inhibit the growth of said tumor when administered by intratumoral injection.
Alternatively, it comprises:
(a) at least one antineoplastic agent in an amount effective to inhibit the growth of said tumor when administered by intratumoral injection; and
(b) a poly(phosphoester) biodegradable polymer made by a process comprising the steps of:
(1) reacting at least one heterocyclic ring compound with
Hxe2x80x94Yxe2x80x94Lxe2x80x94Yxe2x80x94H,
xe2x80x83wherein
H is hydrogen;
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94NR4xe2x80x94, where R4 is H or alkyl; and
L is a divalent, branched or straight chain aliphatic group having 1-20 carbon atoms to form a prepolymer;
(2) further reacting the prepolymer with a phosphorodihalidate to form a poly(phosphoester).
The invention also comprises an article suitable for the intratumoral administration of an antineoplastic agent to a mammal having a solid tumor wherein the article comprises:
(a) a biodegradable poly(phosphoester); and
(b) at least one antineoplastic agent in an amount effective to inhibit the growth of said tumor when administered by intratumoral injection.
In yet another embodiment of the invention, a method is provided for treating a thoracic tumor in a mammal by the intratumoral administration of a composition comprising:
(a) a biodegradable polymer;
(b) at least one antineoplastic agent in an amount effective to inhibit the growth of said tumor when administered by intratumoral injection.
An alternative method for treating a solid tumor in a mammal is by the intratumoral administration of a composition comprising:
(a) a poly(phosphoester) biodegradable polymer;
(b) at least one antineoplastic agent in an amount effective to inhibit the growth of said tumor when administered by intratumoral injection.
The compositions of the invention can be used to deliver a wide variety of antineoplastic agents, for example, both hydrophobic drugs, such as paclitaxel, to large water-soluble macromolecules, such as proteins or DNAs, over an extended period of time without necessitating significant volumes of a delivery fluid or regular re-dosing. The methods of the invention can thus be used to significantly increase the time period over which an effective dose of the antineoplastic agent is released. Further, tumor growth is slowed to an unexpected degree. Further, the tumor suffered by the subject can be therapeutically managed with a minimum of side effects and without the unpleasantness and discomfort of a periodic series of parenteral treatments continuing to maintain a significant concentration of antineoplastic agent within the tumor.